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Author: Anoma Ranaweera, Medical Writer, Auckland, New Zealand, 2013.
Dabrafenib (TAFINLAR™ capsule) was approved by the US Food and Drug Administration (FDA) in 2013 for the treatment of patients with non-operable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Concurrent with this action, FDA approved the THxID BRAF assay (bioMerieux, Inc. USA) for detection of BRAF V600E. Dabrafenib has also been approved by the EMA in the European Union and TGA in Australia for unresectable or metastatic melanoma, and as an adjuvant treatment for melanoma following resection of involved lymph nodes with the BRAF mutation. Other approved indications include anaplastic thyroid cancer and non-small cell lung cancer with the same BRAF mutation.
In November 2015, the FDA also approved the combination of dabrafenib and trametinib for the treatment of metastatic melanoma.
BRAF mutations occur in 50% of melanomas. BRAF inhibitors such as dabrafenib target mutant BRAF and inhibit the MAPK signalling pathway, which mediates cell growth and survival. They are not effective in non-mutant (wild-type) BRAF tumours.
Dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma because of the potential risk of tumour promotion.
The recommended dose is 150 mg orally twice daily taken at least 1 hour before or at least 2 hours after a meal.
In clinical trials, adverse events were common but rarely led to dose reduction or discontinuation.
Most frequent toxicities (ranging from 15% to 33%) included:
Cutaneous side effects include:
Serious adverse events included:
Dabrafenib can cause fetal harm when administered to a pregnant woman (Pregnancy Category D). The patient should be warned of the potential hazard to the fetus, if this drug is used during pregnancy or if the patient becomes pregnant while taking this drug.
The safety and effectiveness of dabrafenib have not been established in children.
No formal pharmacokinetic trial in patients with hepatic or renal impairment has been conducted.
Dabrafenib is primarily metabolised by hepatic enzymes CYP2C8 and CYP3A4. Strong inhibitors or inducers of CYP3A4 or CYP2C8 may increase or decrease, respectively, concentrations of dabrafenib.
If concomitant use of strong inhibitors (e.g. ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, patients should be monitored closely for adverse reactions or loss of efficacy.
Coadministration of dabrafenib with warfarin, dexamethasone, or hormonal contraceptives, can also result in decreased concentrations and loss of efficacy.
Drugs that alter the pH of the upper gastrointestinal tract (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) may alter the solubility of dabrafenib and reduce its bioavailability. However, no formal clinical trial has been conducted to evaluate the effect of gastric pH-altering agents on the systemic absorption of dabrafenib.
Dabrafenib and vemurafenib are both selective type 1 BRAF inhibitors with proven efficacy in BRAF V600E metastatic melanoma. They share many attributes, including clinical activity and class-defined toxicity; however, differences between the drugs exist.
In patients with BRAFmut metastatic melanoma, dabrafenib confers high response rates and an improved overall survival rate over chemotherapy, with a mild, manageable toxicity profile. However, the duration of benefit is usually brief because of the development of acquired resistance.
Combination therapies targeting multiple components of cell signalling, such as CombiDT (combination of dabrafenib with trametinib [an MEK inhibitor manufactured by GSK and approved by US FDA]), has shown higher response rates and more durable clinical benefit than dabrafenib monotherapy. The combination of dabrafenib and trametinib, Mekinist™, was provisionally approved by the FDA for unresectable and metastatic melanoma with BRAF V600E or V600K mutations, in 2014 with regular approval in November 2015.
As both drugs target the MAPK pathway, the combined blockade may circumvent or delay acquired resistance because of reactivation of the MAPK pathway.
If you are not based in New Zealand, we suggest you refer to your national drug approval agency for further information about medicines (eg, the Australian Therapeutic Goods Administration and the US Food and Drug Administration) or a national or state-approved formulary (eg, the New Zealand Formulary and New Zealand Formulary for Children and the British National Formulary and British National Formulary for Children).
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